1. Field of the Invention
The present invention is directed to methods of diagnosing, prognosing, and monitoring the course of arthritis in a subject based on increased protein kinase C zeta (ζPKC) gene expression in arthritic tissue. The present invention further provides compounds that inhibit the expression of ζPKC for use as remedies in the treatment of arthritis.
2. Related Background Art
Protein kinase C zeta (ζPKC) is emerging as an important signal transduction component. There is growing literature suggesting that ζPKC is involved in the NF-κB and AP-1 pathways. For example, a ζPKC knockout mouse is fully viable but displays a phenotype reminiscent of the tumor necrosis factor (TNF) receptor and lymphotoxin receptor knockouts, with severe impairment of NF-κB-dependent transcriptional activity (Leitges et al. (2001) Mol. Cell 8:771-80). Other investigators (Lallena et al. (1999) Mol. Cell. Biol. 19:2180-88) have shown a role for ζPKC in activating IκB and, thereby, activating NF-κB.
NF-κB activation has been implicated in numerous inflammatory disorders, including asthma, inflammatory bowel disease, and arthritis (reviewed in Roshak et al. (2002) Curr. Opin. Pharmacol. 2:316-21). NF-κB has been shown to play an essential role in the secretion of various matrix metalloproteinases (MMPs) from various cell types (Bond et al. (1998) FEBS Lett. 435:29-34; Bond et al. (1999) Biochem. Biophys. Res. Commun. 264:561-67; Bond et al. (2001) Cardiovasc. Res. 50:556-65). In arthritis, cytokines such as TNF and interleukin-1 (IL-1) increase the production and synthesis of MMPs and other degradative enzymes above levels that can be naturally controlled, resulting in disease (reviewed in Smith (1999) Front. Biosci. 4:D704; Mort and Billington (2001) Arthritis Res. 3:337-41; Catterall and Cawston (2003) Arthritis Res. Ther. 5:12-24).
To date, there has been no direct evidence linking ζPKC to arthritis. If ζPKC were expressed in affected tissues, however, it would help to explain the degradative actions of TNF and IL-1 by transducing the extracellular receptor binding of these factors to the intracellular induction of synthesis of degradative enzymes by NF-κB. In this regard, inhibitors of ζPKC may block TNF and IL-1 action and serve as treatments for arthritis and other inflammatory diseases. Such ζPKC inhibitors should be more efficacious than traditional cytokine and MMP inhibitors because they should ultimately affect more than just one target (Roshak, supra; Smith, supra). Such ζPKC inhibitors should also be safer than NF-κB inhibitors because ζPKC is only one of many effectors in the NF-κB pathway.